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CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance and clinical relevance; stresses on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

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Program Educational Objectives As a result of this session, emergency physicians will: As a result of this session, emergency physicians will: Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines As a result of this session, emergency physicians will: As a result of this session, emergency physicians will: Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines

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Changing the Calculation Assessing Adherence to Guidelines Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9. We need to invert the current equation to calculate an opportunity score for ACS patients rather than a risk score. Patients with higher baseline risks, such as the elderly, would have higher opportunity scores for benefit, even allowing for some of the greater risks from the treatment.

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We Must Risk Stratify Patients with Chest Pain Three levels of risk stratification are pertinent to Emergency Department Management Three levels of risk stratification are pertinent to Emergency Department Management Low, intermediate, or high risk that ischemic symptoms are a result of CAD Low, intermediate, or high risk of short-term death or nonfatal MI from ACS Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment Three levels of risk stratification are pertinent to Emergency Department Management Three levels of risk stratification are pertinent to Emergency Department Management Low, intermediate, or high risk that ischemic symptoms are a result of CAD Low, intermediate, or high risk of short-term death or nonfatal MI from ACS Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment

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What Do The Guidelines Mean for Emergency Medicine Practice? Objective approach to risk stratification and treatment Objective approach to risk stratification and treatment Driven by risk, not patient geography Driven by risk, not patient geography Multidisciplinary Multidisciplinary Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service 2007 Guidelines push for that continuum to be compressed in duration 2007 Guidelines push for that continuum to be compressed in duration Objective approach to risk stratification and treatment Objective approach to risk stratification and treatment Driven by risk, not patient geography Driven by risk, not patient geography Multidisciplinary Multidisciplinary Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service 2007 Guidelines push for that continuum to be compressed in duration 2007 Guidelines push for that continuum to be compressed in duration

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AcuteCoronarySyndromeAcuteCoronarySyndrome What Do The Guidelines Mean for Emergency Medicine Practice?

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Acute Confounded Syndrome The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. Acute Confounded Syndrome The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

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AcuteContentiousnessSyndromeAcuteContentiousnessSyndrome What Do The Guidelines Mean for Emergency Medicine Practice?

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Big Picture: Early Invasive Vs. Initial Conservative Therapy An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events. In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including those who are troponin positive. The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference. Big Picture: Early Invasive Vs. Initial Conservative Therapy An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events. In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including those who are troponin positive. The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

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Algorithm for Evaluation and Management of Patients Suspected of Having ACS ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. A A Symptoms Suggestive of ACS NoncardiacDiagnosisNoncardiacDiagnosisUnstableAnginaUnstableAngina Treatment as indicated by alternative diagnosis See ACC/AHA Guidelines for Chronic Stable Angina BI B2 PossibleACSPossibleACS DefiniteACSDefiniteACS B3 B4

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New Strategies: Anticoagulants Two new anticoagulants, fondaparinux and bivalirudin, have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular- weight heparins (LMWHs) for specific or more general applications. New Strategies: Anticoagulants Two new anticoagulants, fondaparinux and bivalirudin, have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular- weight heparins (LMWHs) for specific or more general applications. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

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Welcome To This Program! Move from confusion, controversy, and contentiousness to collaboration and more evidence-based careMove from confusion, controversy, and contentiousness to collaboration and more evidence-based care Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to:Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to: l (1) Treat patients optimally and; l (2) Work effectively and collegially with their cardiology consultants Move from confusion, controversy, and contentiousness to collaboration and more evidence-based careMove from confusion, controversy, and contentiousness to collaboration and more evidence-based care Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to:Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to: l (1) Treat patients optimally and; l (2) Work effectively and collegially with their cardiology consultants

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Recent Clinical Trials in STEMI and NSTEMI What New Evidence Tells Us and Implications for ED Cardiovascular Management Judd E. Hollander, MD Professor and Clinical Research Director Department of Emergency Medicine University of Pennsylvania Getting in the Stream of Things

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ACS: Recent Clinical Trials in STEMI and NSTEMI Getting in the (Up)Stream of Things

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STEMI Conclusions There is still a role for fibrinolytic therapy in STEMI There is still a role for fibrinolytic therapy in STEMI Adjuvant clopidogrel and/or enoxaparin improve outcomes in combination with fibrinolytics Adjuvant clopidogrel and/or enoxaparin improve outcomes in combination with fibrinolytics Fondaparinux improves outcomes relative to placebo Fondaparinux improves outcomes relative to placebo

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ACS: Recent Clinical Trials in STEMI and NSTEMI Getting in the (Up) Stream of Things

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Enoxaparin was not superior to unfractionated heparin but was noninferior for non–ST-segment elevation ACS Enoxaparin was not superior to unfractionated heparin but was noninferior for non–ST-segment elevation ACS More bleeding was observed with enoxaparin More bleeding was observed with enoxaparin Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high- risk patients being managed with a rapid transition to intervention Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high- risk patients being managed with a rapid transition to intervention Do not change from Do not change from l UFH to Enoxaparin, or l Enoxaparin to UFH Stay with the agent initiated in the ED Stay with the agent initiated in the ED l Collaboration l Pathways l Bivalirudin may be exception SYNERGY: Conclusions/Caveats

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Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined ACUITY Conclusions

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NSTEMI Conclusions Old and new options for ACS Old and new options for ACS l UFH or Enoxaparin l Bivalirudin l Fondaparinux (not tested adequately in cath lab) Balance ischemic efficacy and safety Balance ischemic efficacy and safety l Customize approach for patient and institution Many choices Many choices l Collaborate with IC and CARD on clinical pathways Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) Old and new options for ACS Old and new options for ACS l UFH or Enoxaparin l Bivalirudin l Fondaparinux (not tested adequately in cath lab) Balance ischemic efficacy and safety Balance ischemic efficacy and safety l Customize approach for patient and institution Many choices Many choices l Collaborate with IC and CARD on clinical pathways Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM)

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Sea and Stream Changes in ACS The 2007 Guidelines have created a Sea Change in the ED and IC Therapeutic approach to care of patients with UA/NSTEMI The 2007 Guidelines have created a Sea Change in the ED and IC Therapeutic approach to care of patients with UA/NSTEMI New Streams of care, with new anticoagulants, are in play New Streams of care, with new anticoagulants, are in play Clopidogrel use has been liberalized Clopidogrel use has been liberalized Bleeding end points play a more important role in drug selection Bleeding end points play a more important role in drug selection Dogmatism is out, customization is in Dogmatism is out, customization is in Collaboration is emphasized Collaboration is emphasized

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Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class IIb Benefit Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Should Is recommended Is indicated Is useful/effective/ beneficial Is reasonable Can be useful/effective/ beneficial Is probably recommended or indicated May/might be considered May/might be reasonable Usefulness/ effectiveness is unknown/unclear/ uncertain or not well established Is not recommended Is not indicated Should not Is not useful/effective/ beneficial May be harmful Applying Classification of Recommendations

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Either strategy in low- to moderate-risk patients without contraindications to revascularization Early invasive strategy for patients with repeated ACS presentations, without high-risk features or ongoing ischemia Either strategy in low- to moderate-risk patients without contraindications to revascularization Early invasive strategy for patients with repeated ACS presentations, without high-risk features or ongoing ischemia I I IIa IIb III Management Strategies 2002 Guidelines Conservative versus Invasive Strategies

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EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) I I IIa IIb III Management Strategies 2007 Early Invasive versus Initial Conservative

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EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) I I IIa IIb III Management Strategies 2007 Early Invasive vs Initial Invasive

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The decision to employ an EIS vs ICS may be made by considering physician and patient preference Invasive strategy may be preferable in patients with CKD EIS if patient: Will not consent to revascularization Will not consent to revascularization Has too many comorbidities Has too many comorbidities Is low risk Is low risk The decision to employ an EIS vs ICS may be made by considering physician and patient preference Invasive strategy may be preferable in patients with CKD EIS if patient: Will not consent to revascularization Will not consent to revascularization Has too many comorbidities Has too many comorbidities Is low risk Is low risk I I IIa IIb III Management Strategies 2007 Early Invasive versus Initial Conservative

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Medical Management 2007 Guidelines AntiThrombotic Therapy In EIS: Enoxaparin or UFH Enoxaparin or UFH Bivalirudin* or fondaparinux Bivalirudin* or fondaparinux In ICS: In ICS: Enoxaparin or UFH Enoxaparin or UFH Fondaparinux Fondaparinux In ICS with risk of bleeding: Fondaparinux In ICS with risk of bleeding: Fondaparinux In EIS: Enoxaparin or UFH Enoxaparin or UFH Bivalirudin* or fondaparinux Bivalirudin* or fondaparinux In ICS: In ICS: Enoxaparin or UFH Enoxaparin or UFH Fondaparinux Fondaparinux In ICS with risk of bleeding: Fondaparinux In ICS with risk of bleeding: Fondaparinux IIIIaIIaIIbIIbIIIIII

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The ACUITY study, which tested bivalirudin for UA/NSTEMI, has led to a guidelines change to allow bivalirudin as an anticoagulant option. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

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Oral Antiplatelet Therapy 2002 Clopidogrel Guidance Aspirin + clopidogrel, for up to 1 month* Aspirin + clopidogrel, for up to 9 months* Withhold clopidogrel for 5-7 days for CABG Aspirin + clopidogrel, for up to 1 month* Aspirin + clopidogrel, for up to 9 months* Withhold clopidogrel for 5-7 days for CABG IIIIaIIaIIbIIbIIIIII * For patients managed with an early conservative strategy, and those who are planned to undergo early PCI those who are planned to undergo early PCI * For patients managed with an early conservative strategy, and those who are planned to undergo early PCI those who are planned to undergo early PCI Guidelines do not specify initial timing of using Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknown clopidogrel when coronary anatomy is unknown Guidelines do not specify initial timing of using Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknown clopidogrel when coronary anatomy is unknown

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Antiplatelet Therapy Year 2007 Clopidogrel Guidance I I IIa IIb III Clopidogrel with full loading dose in ASA-allergic patients EIS: Clopidogrel or IIb/IIIa administered upstream ICS: Clopidogrel initiated as soon as possible and continued for at least one month...and preferably for one year Clopidogrel with full loading dose in ASA-allergic patients EIS: Clopidogrel or IIb/IIIa administered upstream ICS: Clopidogrel initiated as soon as possible and continued for at least one month...and preferably for one year

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Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: Add IIb/IIIa upstream EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath

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Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned Abciximab for patients in whom PCI is not planned Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned Abciximab for patients in whom PCI is not planned I I IIa IIb III Parenteral Antiplatelet Therapy: 2002 Platelet GP IIb/IIIa Inhibitors

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I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoagulant: Add IIb/IIIa upstream EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors

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ISAR-REACT-2, JAMA 2006 (ACUITY, NEJM 2006) Both of these studies have risk considerations that are important to upstream therapy ISAR-REACT-2, JAMA 2006 (ACUITY, NEJM 2006) Both of these studies have risk considerations that are important to upstream therapy Relevant New Studies Focusing on Antiplatelet Therapy

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Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath

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We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the cath lab. We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the cath lab. There are new agents that will change the ED and the cath lab approach to ACS management, both in terms of pharmacologic stabilization (antithrombotic and antiplatelet therapy) and invasive management (namely, the speed with which the patient goes to the cath lab). There are new agents that will change the ED and the cath lab approach to ACS management, both in terms of pharmacologic stabilization (antithrombotic and antiplatelet therapy) and invasive management (namely, the speed with which the patient goes to the cath lab). Conclusions: NSTE ACS - 2007

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We must work with our colleagues in cardiology to develop pathways for optimal use of antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever feasible, and to address issues related to bleeding risk as well as ischemic risk. We must work with our colleagues in cardiology to develop pathways for optimal use of antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever feasible, and to address issues related to bleeding risk as well as ischemic risk. New (up)streams of care have been introduced and require consideration in ED New (up)streams of care have been introduced and require consideration in ED In ACS management, one size clearly does NOT fit all! In ACS management, one size clearly does NOT fit all! Conclusions: NSTE ACS

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ECG and ASA within 10 min ECG and ASA within 10 min l STEMI patients directed to their pathway Risk stratification Risk stratification l Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilizationPatients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization ECG and ASA within 10 min ECG and ASA within 10 min l STEMI patients directed to their pathway Risk stratification Risk stratification l Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilizationPatients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization Summary 2007 Guidelines: Upstream Management of Suspected ACS

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Anticoagulation Anticoagulation l EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B) Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at hgher risk for bleeding)Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at hgher risk for bleeding) l ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux (I-B) (I-B) Strong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later requiredStrong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later required l Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, which should be made collaboratively by EM and cardiology Summary 2007 Guidelines: Upstream Medical Stabilization

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Anticoagulation Anticoagulation l The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. Summary 2007 Guidelines Upstream Medical Stabilization

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Antiplatelet therapy Antiplatelet therapy l Everybody gets ASA l Clopidogrel use much more strongly supported in 2007 Guidelines than in 2002, but CABG caveat still operative! l Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) l Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment with clopidogrel may override other concerns Antiplatelet therapy Antiplatelet therapy l Everybody gets ASA l Clopidogrel use much more strongly supported in 2007 Guidelines than in 2002, but CABG caveat still operative! l Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) l Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment with clopidogrel may override other concerns Summary 2007 Guidelines Upstream Medical Stabilization

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Earlier use of clopidogrelEarlier use of clopidogrel New antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinationsNew antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinations Faster time to cath for NSTE ACS patientsFaster time to cath for NSTE ACS patients More emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the EDMore emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the ED Earlier use of clopidogrelEarlier use of clopidogrel New antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinationsNew antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinations Faster time to cath for NSTE ACS patientsFaster time to cath for NSTE ACS patients More emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the EDMore emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the ED Summary 2007 Guidelines Changes Likely to Impact the ED

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Ischemic Complications Hemorrhage HIT Death MI Urgent TVR Death MI Urgent TVR Major Bleeding Minor Bleeding Thrombocytopenia Major Bleeding Minor Bleeding Thrombocytopenia Composite Adverse Event Endpoints Evolving ED Paradigm for Evaluating ACS Management Strategies Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events! Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events!

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ACS-related Bleeding Relevant Questions for the Emergency Medicine Specialist Who bleeds? Can we risk stratify? Who bleeds? Can we risk stratify? Should bleeding risk affect upstream antithrombotic care? If so, how? Should bleeding risk affect upstream antithrombotic care? If so, how? Is bleeding bad or a necessary evil? Is bleeding bad or a necessary evil? Can blood transfusion correct risks associated with bleeding? Can blood transfusion correct risks associated with bleeding? Does bleeding affect resource use? Does bleeding affect resource use? What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)? What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)?

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Bleeding in ACS Identification Questions to be answered 1] Who bleeds? 1] Who bleeds? 2] What risk factors are predictive of 2] What risk factors are predictive of bleeding? bleeding? 3] How should initial choices for 3] How should initial choices for upstream care be influenced by upstream care be influenced by bleeding risk? bleeding risk? Questions to be answered 1] Who bleeds? 1] Who bleeds? 2] What risk factors are predictive of 2] What risk factors are predictive of bleeding? bleeding? 3] How should initial choices for 3] How should initial choices for upstream care be influenced by upstream care be influenced by bleeding risk? bleeding risk?

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Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia These risk factors can readily be identified during the ED evaluation of a patient with ACS These risk factors can readily be identified during the ED evaluation of a patient with ACS Bleeding Predictors Conclusions

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Questions to be answered Questions to be answered 1] Is bleeding bad or a necessary evil? 2] What is the relationship between bleeding and patient outcomes in ACS? bleeding and patient outcomes in ACS? 3] What initial choices can the ED physician make that are compatible with physician make that are compatible with guidelines and that will reduce bleeding? guidelines and that will reduce bleeding? Questions to be answered Questions to be answered 1] Is bleeding bad or a necessary evil? 2] What is the relationship between bleeding and patient outcomes in ACS? bleeding and patient outcomes in ACS? 3] What initial choices can the ED physician make that are compatible with physician make that are compatible with guidelines and that will reduce bleeding? guidelines and that will reduce bleeding? Bleeding in ACS Consequences

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Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI l Mortality rates are higher among those who bleed l MI rates are higher among those who bleed The risk is dose-dependent with worse bleeding associated with worse outcomes The risk is dose-dependent with worse bleeding associated with worse outcomes This relationship is persistent after robust statistical adjustment for confounders This relationship is persistent after robust statistical adjustment for confounders Decisions made in the ED may affect subsequent bleeding risk, and in turn, clinical outcomes Decisions made in the ED may affect subsequent bleeding risk, and in turn, clinical outcomes Bleeding and Outcomes Conclusions

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Blood transfusion is independently associated with death and re-MI Blood transfusion is independently associated with death and re-MI Transfusion does not correct the adverse impact bleeding and is not an insurance policy for choices made in the ED Transfusion does not correct the adverse impact bleeding and is not an insurance policy for choices made in the ED Blood transfusion is best avoided in ACS patients whenever possible Blood transfusion is best avoided in ACS patients whenever possible Decisions regarding bleeding risk should be part of ED decision-making process Decisions regarding bleeding risk should be part of ED decision-making process Blood Transfusion Conclusions

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The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding l Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other Although these costs are not realized in the ED, the choices made there impact costs downstream Although these costs are not realized in the ED, the choices made there impact costs downstream Bleeding and Costs Conclusions

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What therapeutic options do ED physicans and cardiologists have to balance efficacy (reduced risk for ischemic outcomes) and safety (bleeding)? Bleeding in ACS Question To Be Answered

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New Strategies: Anticoagulants Two new anticoagulants, fondaparinux and bivalirudin, have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular- weight heparins (LMWHs) for specific or more general applications. New Strategies: Anticoagulants Two new anticoagulants, fondaparinux and bivalirudin, have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular- weight heparins (LMWHs) for specific or more general applications. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

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Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4%

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Bleeding Among Patients with ACS Conclusions There are several therapeutic pathways for NSTE ACS care There are several therapeutic pathways for NSTE ACS care The (up)stream of care begins in the emergency department The (up)stream of care begins in the emergency department Choices made in the ED impact downstream events Choices made in the ED impact downstream events l Ischemic complications l Bleeding complications

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ConclusionsBleeding in ACS Certain patient and PCI procedure characteristics predict bleeding Certain patient and PCI procedure characteristics predict bleeding l Age, female gender, CKD l Diabetes and anemia are newly identified risk factors for bleeding among ACS patients Bleeding is associated with worse short and long- term outcomes including death and MI Bleeding is associated with worse short and long- term outcomes including death and MI Blood transfusion is associated with increased mortality in ACS patients Blood transfusion is associated with increased mortality in ACS patients In addition to clinical outcomes, bleeding is associated with increased cost of care In addition to clinical outcomes, bleeding is associated with increased cost of care Certain patient and PCI procedure characteristics predict bleeding Certain patient and PCI procedure characteristics predict bleeding l Age, female gender, CKD l Diabetes and anemia are newly identified risk factors for bleeding among ACS patients Bleeding is associated with worse short and long- term outcomes including death and MI Bleeding is associated with worse short and long- term outcomes including death and MI Blood transfusion is associated with increased mortality in ACS patients Blood transfusion is associated with increased mortality in ACS patients In addition to clinical outcomes, bleeding is associated with increased cost of care In addition to clinical outcomes, bleeding is associated with increased cost of care

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Conclusions Bleeding in ACS Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk

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ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Studies Emergency Medicine and Cardiovascular Specialists Engage in the Acute Collaboration Syndrome From ACS Risk Profiles to Patient Care: Case Studies in ACSDoing the Right Thing in the Right Patient ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Studies Emergency Medicine and Cardiovascular Specialists Engage in the Acute Collaboration Syndrome From ACS Risk Profiles to Patient Care: Case Studies in ACSDoing the Right Thing in the Right Patient Getting in the Stream of Things

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Case Studies in Acute Coronary Syndromes Acknowledgement is made to Dr. Steven Manoukian, MD and CMEducation Resources, LLC for patient cases studies, cineangiograms, and/or assistance in preparation of case studies for this segment of the program

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Which of this patients baseline factors do you consider most important for determining hemorrhagic risk? A. Advanced age B. Hypertension C. Impaired creatinine clearance D. Anemia * Case #1

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In ACS patients, do you alter your choice of anticoagulant/ antithrombotic therapy based upon an assessment of the individual patients risk of hemorrhagic complications? A. Yes B. No * Case #1

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Among those of you who would alter or customize antithrombotic therapy based on an ACS patients risk for hemorrhage in the setting of PCI, which of the following baseline characteristics would you consider most important in supporting the use of a hemorrhage- minimizing anithrombotic regimen: A. Elderly and female B. Renal insufficiency and positive biomarkers C. Anemia and high risk ischemic features * Case #1

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What would you likely use for anticoagulation in this patient, prior to catheterization, if you anticipated catheterization would occur in 4 hours or less? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #1

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Based upon this patients overall profile, when selecting an antithrombotic regimen, you are more likely be concerned about: A. Ischemic risk B. Hemorrhagic risk * Case #2

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Which of the following factors would you consider most important when evaluating the need for immediate catheterization in this patient? A. Advanced age B. Positive biomarkers C. ECG findings D. Refractory discomfort * Case #2

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What would you use for upstream anticoagulation in this patient whose catheterization is planned for the next day: i.e., within 24 hours? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #3

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In general, in an ACS patient with moderate or high risk ischemic features, at what point in the patients course would you administer clopidogrel? A. In the ED, immediately. B. In the catheterization lab, prior to catheterization. C. In the catheterization lab, after catheterization and decision to proceed with PCI, but prior to PCI. D. In the catheterization lab, post-PCI. * Concluding Questions

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In general, based on my interpretation of the current evidence for selecting anticoagulation therapy in ACS patients, therapy is best guided by: A. Ischemic risk (reduction of ischemic endpoints) B. Bleeding risk (reduction of bleeding endpoints) C. Balance of ischemic and bleeding risk, and selection of a strategy that optimizes net clinical benefit (optimizes aggregate reduction of both ischemic and bleeding endpoints) * Concluding Questions

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1) How do ED specialists incorporate new streams of care for NSTEMI introduced by Year 2007 ACC/AHA Guidelines for NSTEMI - Bivaliridion for initial invasive strategy? Fondaprinux for initial conservative therapy? 2) How do new guidelines affect clopidogrel treatment at front lines of ED care? 3) How do ED specialists and cardiologists synchronize on new GLs and newly introduced options? 4) Questions * Discussion Points